Asthma is a non-infectious chronic inflammatory disease of the respiratory system characterized by a reversible airways obstruction. Acute airway obstruction, bronchial hyper-responsiveness and inflammatory state of the bronchial mucosa with increase levels of inflammatory mediators, are the most evident phenomenon which characterizes this pathology. Despite the increase in the prescribed anti-asthmatic treatments, the current trends indicate asthma is set to be the most chronic disease in industrialized countries, affecting mostly the children (10%) than the adults (15%).
Chronic obstructive pulmonary disease (COPD) is the most common of all the respiratory disorders in the world, which embraces several inflammatory pathologies that often co-exist. The WHO predicts COPD (Donnelly, L. E.; Rogers, D. F., Therapy for COPD in the 21st century, Drugs, 63, 1973-1998, 2003) will become the third most common cause of death world over by 2020 accounting 8.4 million lives. Although asthma for the last 25 years has been managed therapeutically, with a combined bronchodilator and anti-inflammatory therapies, in contrast to this COPD have no effective treatments currently, while the efficacy of the corticosteroids is controversial. Hence, there is an urgent need to develop novel anti-inflammatory drugs having both the bronchodilatory and anti-inflammatory activity, having applicability to treat both COPD as well as asthma. Thus, the development of therapies for bronchial asthma has become the major focus of the pharmaceutical industry in the field of respiratory disorders.
References may be made to journals Yeoung, K,-P; Drug Discovery Today 14, 812-813, 2009; Houslay, M. D.; Schafer, P.; Zhang, K, Y, J. Drug Discovery Today 10, 1503-1519, 2005; Dal Piaz, V.; Giovannoni, M. P., Eur. J. Med. Chem., 35, 463-480, 2000; Giembycz, M. A. Monaldi Arch Chest Dis. 57, 48-64, 2002; Molfino, N. A., Respiration 72, 105-112, 2005; Conti, M.; Beavo, J. Annu. Rev. Biochem., 76, 481-511, 2007, wherein development of novel PDE-4 inhibitors and its therapeutic applications was reported. PDEs are a large family of enzymes that metabolise the second messenger cAMP/cGMP into inactive acyclic systems. The role of cAMP as a second messenger is well established and it modulates the response of immune cells to a variety of stimuli. Elevation of cAMP has generally been associated with inhibition of lymphocyte activity. The elevation of cAMP levels leads to the suppression of the synthesis and release of pro-inflammatory signals, cytokines and inhibit the production of reactive oxygen species.
The PD enzymes are a large family with eleven sub-families. Of these, the PDE-4, 7 and 8 are associated with the metabolism of cAMP. PDE-4 has four distinct genes, PDE-4A, PDE-4B, PDE-4C and PDE-4D (Muller, T.; Engels, P.; Fozard, J. R. Trends Pharmacol. Sci., 17, 294-298, 1996) with specificity to cAMP and thus have become potential therapeutic targets and most of the research is centred on PDE-4 inhibitors (Teixeira, M. M.; Gristwood, R. W.; Cooper, N.; Hellewell, P. G. PDE-4 inhibitors: Trends Pharmacol. Sci., 18, 164-170, 1997). PDE-4 is the selective phosphodiesterase enzyme that metabolises the cAMP. Hence, PDE-4 inhibitors prevent the inactivation of cAMP.
The presence of PDE 4 inhibitor in natural product has also been reported earlier. Mesembrine, a major alkaloid present in Selectium torouosum, has been shown to act as a PDE-4 inhibitor (Smith, M.; Crouch, N.; Gericke, N.; Hirst, M. Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: review. J. Ethnopharmacol 50, 119-30, 1996; Pharmaceutical compositions containing mesembrine and related compounds. U.S. Pat. No. 6,288,104). This is the first catechol based natural product that showed PDE-4 activity. Theophylline is the oldest and shows a weak and non-specific PDE inhibition. Rolipram is the most effective PDE-4 inhibitor, since its discovery, (Griswold, D. E.; Webb, E. F.; Breton, J.; White, J. R.; Marshall, P. J.; Torphy, T. J., Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response, Inflammation 17, 333-44, 1993; Schneider, H. H.; Schmiechen, R.; Brezniski, M.; Seidler, J.; Eur. J. Pharmocol., 127, 105-115, 1986). It is a catechol based compound and structurally related to mesembrine. Rolipram, thus has become a template for the synthesis of novel inhibitors, besides becoming a reference drug in evaluating other inhibitors. Ariflo (cilomilast, SB-207,499; Profita, M, Chiappara G, Mirabella, F Chimenti, G Di, L, Costanzo, G, Riccobono, L Bellia V, Bousquet J, and Vignola A. Effect of cilomilast (Ariflo) on TNF-, IL-8 and GM-CSF release by airway cells of patients with COPD. 58, 573-579, 2003. Ochiai, H.; Ohtani, T.; Ishida, A.; Kusumi, K.; Kato, M.; Kohno, H.; Kishikawa, K.; Obata, T.; Nakai, H.; Toda, M. Bioorg. Med. Chem. Lett., 14, 207-10, 2004), roflumilast (Hatzelmann, A.; Schudt, C. J. Pharmacol. Exp. Ther. 297, 267-290, 2001), CDP-840, HT-0712, filaminast are some of the rolipram related active PDE-4 molecules, while V-11294A which is in phase-II clinical trials represents a hybrid molecule of xanthine and rolipram. Cilomilast, roflumilast, BAY-19-8004 and arofylline are in phase-III clinical trials. Thus, PDE4 appears an important target for COPD also.
However the most common and worrisome aspect in the PDE-4 inhibitors is their propensity for side effects such as nausea and vomiting. The mechanisms by which the PDE-4 inhibitors induce side effects are uncertain. However, the family of PDE-4 enzymes exist in two different conformational states (Souness, J. E.; Rao, S. Cell Signal, 9, 227-236, 1997; Duplantier, A. J. et al., J. Med. Chem. 39, 120-125, 1996), distinguishable with their affinity towards rolipram: the conformation with low affinity for rolipram is LAR conformation (PDE-4L), while the one with high affinity is known as HAR conformation (PDE-4H). PDE-4L is associated with anti-inflammatory activity, while the PDE-4H conformation correlates with adverse effects such as emesis.